S-triazolo(1,5-d)benzodiazepin-6(7h)-ones

ABSTRACT

S-triazolo(1,5-d)(1,4)benzodiazepin-6(7H)-ones, e.g., 7-methyl10-chloro-5H-s-triazolo(1,5-d)(1,4)benzodiazepin-6(7H)-one are useful as minor tranquilizers, anti-convulsants and sleepinducers.

United States Patent [191 Kathawala Jan. 21, 1975S-TRIAZOLO(1,5-D)BENZODIAZEPIN- 6(7H)-0NES [75] Inventor: Faizulla G.Kathawala, West Orange, NJ.

[73] Assignee: Sandoz, lnc., Hanover, NJ.

[22] Filed: Mar. 5, 1973 [21] Appl. N0.: 338,340

[52] U.S. Cl. 260/2393 T, 424/469, 260/308 R [51] Int. Cl.. C07d 53/06,C07d 55/06, C07d 99/02 [58] Field of Search 260/2393 T [57] ABSTRACTStriazolo[ l ,5-d][ l,4]benz0diazepin-6(7H )-0nes, e.g.,7-methyll0-chloro-5H-s-triazol0[1,5- d][l,4]benzodiazepin-6(7H)-one areuseful as minor tranquilizers, anti-convulsants and sleepinducers.

24 Claims, N9 Drawings S-TRlAZOLOt l 5-1))BENZODIAZEIIN- 6(7H J-ONESwhere R, and R, each independently represent hydrogen, halo having anatomic weight of about 18 to 80, lower alkyl, i.e. alkyl having 1 to 4carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and the like,provided that a least one R and R is halo, preferably chloro, when R ishydrogen; and

R is hydrogen, lower alkyl as defined above; and

R is hydrogen, lower alkyl as defined above, unsubstituted phenyl orphenyl mono-substituted with halo having an atomic weight of 18 to 80,and

R, is hydrogen or lower alkyl as defined above, and

R is hydrogen, lower alkyl as defined above, unsubstituted phenyl ormono-substituted phenyl as defined above.

The compounds of formula (I) may be prepared by the following reactionscheme:

where X is halo having an atomic weight of 35 to 80,

and

where at least one of R and R is hydrogen, and the other is aspreviously defined, and

R,,. R R and R are as defined above.

The compounds of formula (I) may be prepared by treating a compound ofthe formula (ll) with a strong base, such as potassium or sodiumhydroxide, sodium hydride, or an alkali metal alkoxide such as potassiumethoxide or sodium ethoxide, the latter being especially preferred. Thereaction is carried out in an inert polar solvent such as the loweralkanols e.g. methanol, ethanol, and the like, acetonitrile,dimethylformamide, or dimethylacetamide, preferably dimethylacetamide.Although the temperature of the reaction is not critical, it ispreferred that the reaction be run from about -10 to +40C, morepreferably from about 20 to 30C. The.

reaction times may typically run from about 30 to 60 hours.

The compounds of formula (II) may be prepared by the following reactionscheme:

where at least one of R and R is hydrogen, and the other is as definedabove, and

R R,, R R and X are as defined above.

The compounds of formula (II) are prepared by treating a compound of theformula (ill) with a compound of the formula (IV) preferablybromoacetylbromide. in the presence of a mild base. Suitable mild baseswhich may be employed in this reaction include organic bases, e.g.,pyridine or inorganic bases such as sodium carbonate or potassiumcarbonate, the latter being especially preferred. The reaction iscarried out in the presence of an inert organic solvent such as thearomatic hydrocarbons, e.g., benzene, toluene and the.

where at least one of R and R is hydrogen and the other is as definedabove, and

Y is lower alkyl having 1 to 2 carbon atoms, and

R R R R and X are as defined above.

The compounds of formula (I) are prepared by treating a compound of theformula (III) with a compound of the formula (V) in the presence of aninorganic base such as an alkali metal hydroxide, eg sodium hydroxide,potassium hydroxide and the like, of sodium hydride, the latter beingespecially preferred. The reaction is carried out in the presence of aninert organic solvent such as lower alkanols, e.g., methanol, ethanoland the like, dimethyl formamide, dimethyl aeetamide or acetonitrilepreferably dimethylacetamide. The temperature of the reaction is notcritical, but it is preferred that the reaction be run at temperaturesfrom about l0 to 120C, more preferably from about to 30C. The reactionwas typically run from about 30 to 60 hours.

Another aspect of this invention is the preparation of compounds offormula (I) in which R is lower alkyl as defined above, and R and R areas defined above, by

the following reaction scheme:

- H ti 0 W R3 r I R '-C1'H\l N a (v1) I N 1 N k R (In) 5 l i R O l I R3N I 11 R1 q I F (Ic) where R is hydrogen or lower alkyl having 1 to 3carbon atoms and R R R R and R are as defined above.

The compounds of formula (Ic) are prepared by treating a compound of theformula (Ib)with a diazoalkane, of the formula (VI) in the presence ofan inert organic solvent such as ethers, e .g., diethyl-ether, dioxaneor tetrahydrofuran, preferably diethylether or a mixture of ether andalcohol. The reaction temperature is not critical, but it is preferredthat the reaction be run at temperatures from about 0 to 40C, preferably20 to 30C. The reaction may typically run from about 10 to 30 hours.

The compounds of formula (I) in which R is other than hydrogen and oneor more of R R or R is lower alkyl may be prepared by the followingreaction scheme A:

I R21 I Z N\ 1; base R2 Re i o R N R \N 1 it. I

lIe) 5 R T2 N o N R II I h NA l where R is lower alkyl having I to 4carbon atoms,

where R is the same as R excluding hydrogen and represent R when R ishydrogen,

where each of R and R is respectively the same as R, and R excludinghydrogen and are respectively R when either of R and R are hydrogen, andZ is a leaving group such as chlorine, bromine, tosyl or mesyl and R R,,R R R and R are as defined above. The compounds of formula (Id) (Ie),and (If) are prepared in the reaction scheme by treating a compound ofthe formula (I) with an alkylhalide of the formula R 'Z such asmethyliodide, ethyliodide, methylbromide and the like, preferablymethyliodide in the presence of a base e.g., sodium hydroxide, potassiumhydroxide or sodium hydride the latter being especially preferred. Thereaction is carried out in the presence of an inert polar solvent suchas the lower alcohols, e.g., methanol, ethanol and the like,dimethylformamide or dimethylacetamid, the latter being especiallypreferred. The reaction temperature is not critical, but it is preferredthat the reaction be carried out between about 0 to 40C, preferablyabout to 30C. In reaction scheme A, it will be evident that the maximumnumber of three products, i.e., products of the formula (Id), (Ie) and(If) are produced only when all of R R and R in the compound (I) arehydrogen. If one of R R and R is other than hydrogen, then only two ofsuch products will, of course, be produced and one of such products iftwo of R R and R are other than hydro gen. My observations of thereaction of reaction scheme A indicate that the 7-position nitrogen atomand 5-position carbon are both highly receptive to reaction with thealkyl halide, and that the use of even the lower mol ratios of the alkylhalide and Base (e.g., sodium hydride) to compound (I) will result inmixture of the products which can be formed in view of the definition ofR R and R in the compound (I). It will, however, be evident that theratio in which the products of the formulae (Id), (Ie)and/or (II) areformed will depend upon known variables, particularly the reaction timeand the mol ratio of the alkyl halide and Base (e.g., sodium hydride),to compound, and that the higher mol ratios and very extended reactiontimes may be employed to produce a reaction product which is largely oressentially exclusively a compound of the formula (I) in which all ofthe positions, R R and R are other than hydrogen.

The compounds of formulas (1), (lb), (lc), (Id), (Ie), (If) and (II) maybe recovered using conventional techniques such as crystallization,filtration or column chromatography.

Certain of the compounds of the formulas (III), (IV), (V), and (VI) areknown and may be prepared by methods disclosed in the literature. Thosecompounds (III), (IV), (V), and (VI) not specifically disclosed may beprepared by analogous methods from known starting materials.

The compounds of formula (I) possess pharmacological activity. Inparticular, they possess central nervous system depressant activity,particularly minor tranquilizing and anti-convulsant activity asindicated 1) by their ability to produce docility in behavior tests inmice given 50 to 250 mg/kg i.p. of the test compound according to the30-word adjective check sheet system, basically as described by S.Irwin, Gordon Research Conference, Medicinal Chemistry, 1959 and Chem.,Symposium on Sedative and Hypnotic Drugs, Williams and Wilkins, 1954; 2)by the hexobarbital reinduction method of Winter, J. Pharmacol, and Exp.Therap., 94, 7-1], 1948 and (3) by their ability to antagonize tonicconvulsions and death in mice given 50 to 250 mg/kg, i.p. of the testcompound followed 1 hour later by 50 mg/kg i.p. of N-sulfamoylazepine.

The compounds of formula (I) in which R is alkyl are also useful assleep inducing agents as indicated in Cebus monkey using chronicallyimplanted electrodes. Brain readings are obtained via a 10 or 16 channelelectroencephalagraph.

For the recording sessions, the monkeys are restrained by neck and waistplates in chairs in full side observation cages at the same time everynight for 13% hours Monday through Thursday. Gross behavior is monitoredvia closed circuit television and video tape recordings.

The compound of formula (I) is administered p.o. immediately on placingthe monkey in the observation cages with at least 7 days interveningbetween drug administration. Physiological saline is administered via asimilar route and at the same times on all control runs.

Control data are collected at least 3 days per week and accumulated togive control data for 15 sessions per monkey Data from each session arestatistically compared via computer analysis to the previous 5-l5control sessions for the particular animal, with particular emphasisgiven to the following phases of the sleepwakefulness cycle: restingawake, light sleep, deep sleep, paradoxical (REM) sleep, pseudo-"paradoxical sleep, latency to onset of deep sleep, and latency .to onsetof first epoch of paradoxical sleep.

For such usage, the compounds of formula (I) may be administered orallyor parenterally as such or admixed with conventional pharmaceuticalcarriers. They may be administered orally in such forms as tablets,dispersible powders, granules, capsules, syrups and elixirs, andparenterally as solutions e.g., a sterile injectable aqueous solution.The compositions for oral use may contain one or more conventionaladjuvants, such as sweetening agents, flavoring agents, coloring agentsand preserving agents, in order to provide an elegant and palatablepreparation. Tablets may contain the active ingredient in admixture withconventional pharmaceutically acceptable excipients, e.g., inertdiluents, such as calcium carbonate, sodium carbonate, lactose, andtalc, granulating and disintegrating agents, e.g., starch and alginicacid, binding agents, e.g., starch, gelatin and acacia, and lubricatingagents, eg., magnesium stearate, stearic acid and talc. The tablets maybe uncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. Similarly, suspensions, syrups, andelixirs, may contain the active ingredient in admixture with any of theconventional excipients utilized for the preparation of suchcompositions, e.g,, suspending agents (lecithin, polyoxyethylenestearate and polyoxyethylene sorbitan monoleate) and preservatives(ethyl-phydroxybenzoate). Capsules may contain the active ingredientalone or admixed with an inert solid diluent, e.g., calcium carbonate,calcium phosphate and kaolin. The injectable compositions are formulatedas known in the art. All these pharmaceutical preparations may containup to about of the active ingredient in combination with the carrier oradjuvant.

Furthermore, the compounds of formula (I) may be similarly administeredin the form of their non-toxic pharmaceutically acceptable acid additionsalts. Such salts possess the same order of activity as the free base,

are readily prepared by reacting the base with an appropriate acid andaccordingly, are included within the scope of the invention.Representative of the acid addition salts are the mineral acids salts,such as the hydrochloride, hydrobromide, sulfate and phosphate and thelike and the organic acid salts such as succinate benzoate, acetate,p-toluenesulfonate, benzenesulfonate, and the like.

For the above indicated use as a minor tranquilizer and as ananti-convulsant, the dosage of compound (I) 10 will vary depending uponthe mode of administration utilized and the particular compoundemployed. However, in general, satisfactory results are obtained whenthe compounds are administered at a daily dosage of from about 4milligrams to 200 milligrams per kilogram of animal body weight. Thisdaily dosage is preferably given in divided doses, e.g., 2 to 4 times aday, or in sustained release form. For most large mammals, the totaldaily dosage is from about 300 to 3,000 milligrams, and

dosage forms suitable for internal administration comprise from about 75milligrams to about 1,500 milligrams of the compound in admixture with asolid or liquid pharmaceutical carrier or diluent.

The sleep inducing effective dosage of the compounds of the formula (I)will vary depending on the particular compound employed. However, ingeneral, satisfactory results are obtained when the compounds areadministered orally at a daily dosage of from about 2 milligrams toabout 100 milligrams per kilogram of animal body weight, typically givenin a single dose at bedtime. For most large mammals, the total dailydosage is from about 150 to about [,000 milligrams, preferably atbedtime and dosage forms suitable for internal administration comprisefrom about 75 to about 500 milligrams of the compound in admixture witha solid or liquid pharmaceutical carrier or diluent. The preferredpharmaceutical compositions from the standpoint of preparation and easeof administration are solid compositions, particularly hard-filledcapsules and tablets.

Tablets and capsules containing the ingredients indicated below may beprepared by convention techniques and are useful as sleep inducers at adose of one or two tablets just before bedtime.

Weight (mg) Ingredients, tablet capsule 7-methyl-lO-chloro-5H-s triazolo200 200 [l.5-d]l l,4 l-benzodiazepin-(r (7H)-one. tragacanth l0 lactose247.5 300 corn starch 25 talcum l5 magnesium stearate 2.5 Total 500 mg.500 mg.

EXAMPLE l ually allowed to warm up to room temperature and stirred for aperiod of 48 hours. Thereafter the dimethylacetamide is removed in vacuoand the resulting residue is dissolved in water. The pH of the solutionmade neutral (7.0) by small additions of hydrochloric acid and extractedseveral times with ethylacetate. The combined ethylacetate extracts arewashed 2 times with water, dried over sodium sulfate, filtered andevaporated in vacuo to dryness. The residue from the above is thenchromatographed on silica gel. Elution is started with methylenechloride and subsequently with methylene chloride containing increasingamounts of methanol. The fractions containinglO-chloro-SH-striazolo[1,5-d][ l,4]benzodiazepin-6(7H')-one arecombined. The solvents are removed in vacuo and the product isrecrystallized from ether to give lO-chloro- 5H-s-triazolo[ l ,5-d][ l,4]benz0diazepin-6( 7H)-one, m.p. 225-227C.

Following the above procedure and using in place. of3-(2-amino-5-chlorophenyl)-s-triazole an equivalent amount of a)3-(2-amino-5-chlorophenyl)-5-methyl-s-triazole.

b) 3-(2'-amino-5*chlorophenyl)-5-(ochlorophenyl)-s-triazole,

c) 3-(2'-amino-5-tolyl)-s-triazole,

d) 3-(2'-amino-4,5'-dichlorophenyl)-s-triazole, or

e) 3-(2'-methylaminor5'-chlorophenyl)-s-triazole,

there is obtained 0) 3-(2'-a-bromoacetylamino-5-methyl)-s-triazole.

d) 3-(2'-a-bromoacetylamino-4',4-dichloro-striazole, and

3-(2-N-methyl-a-bromoacetylamino-5' chlorophenyl)-s-triazole,respectively. Step b: d][1,4]benzodiazepin-6(7H)-one A solution ofsodium ethoxide is prepared by dissolving 4.9 grams of sodium in 500 mlabsolute ethanol. To this solution there is then added 56.3 gms of3-(2'- 0 a-bromoacetylamino-S-chlorophenyl)-5-methyl-striazole in 1,800ml of N-N-dimethylacetamide over a period of 5 to 6 hours dropwise. Thereaction mixture is then allowed to stir at room temperature for 48hours.

Thereafter the solvents are removed in vacuo, the residue treated withwater, solution brought to pH 7.0 and extracted several times withethylacetate. The combined ethylacetate extracts are washed 3 times withwater, dried oversodium sulphate, filtered and 50 evaporated in vacuo todryness. The residue is treated l0-chloro-2-methyl-5H-s-triazolo[1,5-

9 b) 10-chloro-2-(o-chlorophenyl)-5H-s-triazolo[1,5-

d][1,4]benzodiazepin-6(7H)-one, c) l-methyl-5H-s-triazolo[1,5

d][ l ,4]benz0diazepin-6( 7H )-0ne, d) 9, l0-dichloro-5H-s-triazolo[1,5-

d][1,4]benzodiazepin-6(7H)-one, and

N-methyl-l0-chloro-s-triazolo[1,5- d][1,4]benzodiazepin-6(7H)-onerespectively.

l0-chloro-2-methyl-5H-s-triazole[1,5- d][1,4]benzodiazepin-6(71-l)-one,b) 10-chloro-2-o-chlorophenyl-5H-s-triazolo[1,5-

d][ l,4]benzodiazepin-6(7H)-one,

lO-methyl-H-s-triazolo[1,5- d][ 1,4]benzodiazepin-6(7H)-one, d)9,10-dichloro-5H-s-triazolo[1,5-

d][ l,4]benzodiazepine-6(7H) -one, and

7-methyl-l0-chloro-5H-s-triazolo[1,5- d][1,4]benzodiazepin-6(7H)-one,respectively.

EXAMPLE 2 Step a: 3-(2-a-bromoacetylamino-5'-chlorophenyl)-5-methyl-s-triazole To a solution of 60 gms. of 3-(2'-amino-5-chlorophenyl)-5-methyl-s-triazole in 1500 ml absolute tetrahydrofuranthere is added 20 grns. of anhydrous potassium carbonate and then asolution of 48 gms of bromoacetylbromide in 50 ml tetrahydrofuranedropwise. After the addition, the reaction mixture is stirred at roomtemperature for 1 hour. Thereafter, the reaction mixture is evaporatedin vacuo, the residue treated with water and then with small portions ofsodium hydroxide solution until the pH of the solution if 7.0. Theresultant mixture is then extracted with methylenechloride and the firstamount of desired material which began to crystallize is filtered off,washed well with water and methylene chloride. The methylene chlorideextracts are combined, washed three times with water, dried over sodiumsulphate, filtered and evaporated in vacuo to dryness. The residue iscrystallized from ether and 32 gms. of 3-(2'a-bromoacetylamino-S'-chlorophenyl)-5-methyl'striazole is obtained.

Following the above procedure and using in place of3-(2'-amino-5'-chlorophenyl)-5-methyl-s-triazole an equivalent amount ofa) 3-(2'-amino-5 '-chlorophenyl)-s-triazole, b)3-(2-amino-5'-chlorophenyl)-5-(ochlorophenyl)-s-triazole, c)3-(2-amino-5-tolyl)-s-triazole, d)3-(2'-amino-4',5-dichlorophenyl)-s-triazole, or e)3-(2-methylamino-5-chlorophenyl)-s-triazole,

there is obtained 3-(2'-a-bromoacetylamino-5-chlorophenyl)-striazole, b)3-(2'-a-bromoacetylamino-5-chlorophenyl)-5-ochlorophenyl-s-triazole,Step b: l0-chloro-2-methyl-5H-s-triazolo[1,5- d][l,4]benzodiazepin-6(7H)-one A solution of sodium ethoxide is prepared bydissolving 4.9 grams of sodium in 500 ml absolute ethanolv To thissolution is then added 56.3 gms of3-(2'-abromoacetylamino-S'-ehlorophenyl)-5-methyl-striazole in 1800 mlof N-N-dimethylacetamide over a period of 5 to 6 hours dropwise. Thereaction mixture is then allowed to stir at room temperature for 48hours.

Thereafter the solvents are removed in vacuo, the residue treated withwater, solution brought to pH 7.0 and extracted several times withethylacetate. The combined ethylacetate extracts are washed 3 times withwater, dried over sodium sulphate, filtered and evaporated in vacuo todryness. The residue is treated with pentane/ether to give the firstcrop of solids. These solids are crystallized from methylene chloride togive 4.0 gms of 2methyl-l0-chloro-5-l-l-s-triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one m.p. 225-58C.

Following the above procedure and using in place of3-(2-a-bromoacetylamino-5-chlorophenyl)-5- methyl-s-triazole, anequivalent amount of a) 3-( 2 -a-bromoacetylamino-5 -chlorophenyl)-striazole, b) 3(2-a-bromoacetylamino-5 -chlorophenyl-5-o-' andEXAMPLE- 3 7-methyl-l0-chloro-5H-s-triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one To a solution of 2 grams ofl0-chloro'5H-s-triazolo- [l.5-d][ l,4]benzodiazepin-6(7H)-one in 250 mlmethanol there is added a solution offreshly prepared diazomethane in mlether (diazomethane prepared from 16.8 gms. N-nitrosomethylurc at roomtemperature) and the solution is stirred at room temperature for 18hours. Excess diazomethane is then decomposed by addition of acetic acidand solvents are removed in vacuo. The residue is then treated with2N-sodium carbonate solution until the pH of the mixture is 7.0 and thenextracted several times with ethyl acetate. The combined ethyl acetateextracts are washed 3 times with water, dried over sodium sulfate andfiltered. The solvent is evaporated in vacuo and'the residue is thenchromatographed on silica gel with chloroform containing increasingamounts of methanol. The fractions are collected and the solvents areevaporated in vacuo. The residue is recrystallized from ether to give1.2 gm of 7- methyl-10-chloro-5H-s-triazolo [1,5-d][l,4]benzodiazepin-6( 7H)-one m.p. -144.

EXAMPLE 4 l0-chloro-7-methyl-5H-s-triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one and l0-chloro-5,7-dimethyl-5H-s-triazolo[l,5-d][1,4]benz0diazepin- 6(7H)-one andl0chloro-5,5,7-trimethyl5H-striazolo[ l ,4-d][ l,4]benzodiazepin-6(7H)-one.

To a solution of 4.7 grams of l0-ehloro-5l-l-striazolo[l .5-d][l,4]benzodiazepin-6(7l-l)-one in 50 ml of N-N-dimethylacetamide there isadded 1.92 grams 10-dichloro-SH-s-triazolo[1,5-

of57% sodium hydride dispersed in mineral oil; and the reaction mixtureis stirred at room temperature for 1 hour. Thereafter, there is added 3ml. methyliodide, and the mixture is stirred at room temperature for 2hours. The solvent is then removed in vacuo and the residue is dissolvedwith water. The pH is adjusted to 7.0 and the mixture is extractedseveral times with ethyl acetate. The combined ethyl acetate extractsare washed 3 times with water, dried over sodium sulfate, and filtered.The solvent is evaporated in vacuo and the residue is then verycarefully chromatographed on silica gel with methylene chloridecontaining increasing amounts of methanol. The fractions are collectedand the solvents removed in vacuo to obtain the following products:

lO-chloro-7-methyl-5H-s-triazolo[1,5- d][1,5]benzodiazepin-6(7H)-one,l40-l44C. lO=chloro-5,7-dimethyl-5H-s-triazolo[1,5-

d][l,4]benzodiazepin-6(7H)-one mp 138l42C.l-chloro-5,5,7-trimethyl-5l-l-s-triazolo[1,5-

d][1,4]benzodiazepin-6(7H)-one l73-l74C. Following the above procedure,there may be obtained a) l(l-chloro-2,7-dimethyl-H-s-triazoloI1,5-

dll l,4]benzodiazepin-6(7H)-one, m.p. l33l35C.

b) 10 -chloro-2,5,7-trimethyl-5H-striazolol1,5-

d][l .4lbenzodiazepin6(7H)-one m.p. 130135C, and

c) l0-chloro-2,5,6,7-tetramethyl-5H-s-triazolo[1,5-

d][1,4]benzodiazepin-6(7H)-one, l40-143C, respectively.

What is claimed is:

1. A compound of the formula R is hydrogen, alkyl of l to 4 carbonatoms, unsubwhere R,,, R R R and R are as defined in claim I, or apharmaceutically acceptable acid addition salt thereof. 4. A compound ofthe formula I N R3 N Rh 1 l E\ where 01, 7

R is lower alkyl of l to 4 carbon atoms, and R R,, R3, R and R are asdefined in claim 1 or a pharmaceutically acceptable acid addition saltthereof. 5. A compound of the formula R l O N R3 R N c1 7 where R R Rand R are as defined in claim 1, or a pharmaceutically acceptable acidaddition salt thereof. 6. A compound of the formula Cl N where R R and Rare as defined in claim 1, or a pharmaceutically acceptable acidaddition salt thereof. 7. A compound of the formula N 01 I l where v R Rand R are as defined in claim 1, or a pharmaceutically acceptable acidaddition salt thereof.

8. A compound of the formula where R,,, R R and R are as defined inclaim 1, or a pharmaceutieally acceptable acid addition salt thereof. 9.A compound of the formula where R is alkyl of l to 4 carbon atoms, and Ris as defined in claim I, or a pharmaceutically ac- -ceptable acidaddition salt thereof. 10. A compound of the formula CH3 1 l l 1 1 whereR,,, R and R are as defined in claim 1, or a pharmaceutically acceptableacid addition salt thereof.

11. The compound of claim 1 which is IO-chloro-SH- s-triazolo [l,5-d][ l,4]benzodiazepin-6(7l-l)-one.

12. The compound of claim 1 which is l0-chloro-2- methyl-5H-triazolo[l,5-d][ l ,4lbenzodiazepin- 6(7H)-one.

2 R L t n with a compound of the formula:

in the presence of a mild base and an inert organic solvent to obtain anintermediate of the formula:

14% R uc x 3 \R l \N 4 1 u and thereafter reacting said intermediatewith astrong base in the presence of an inert polar solvent wherein atleast one of R; and R is hydrogen and the other is as defined above, andeach x is independently halo having an atomic weight of 35 to 80, and RR R and R are as defined in claim 1. 17. A process for preparing acompound of claim 1 which comprises the step of reacting a compound ofthe formula:

it l R1 N 4-K with a compound of the formula:

in the presence of an inorganic base and an inert organic solvent,wherein at least one of R and R is hydrogen and the other with adiazoalkane of the formula R 'CHN which comprises the step of reacting athe formula compound of K R o 4 R f N 1 l] N with an alkyl halide of theformula in the presence of a base and an inert polar solvent wherein R RR R R and R are as defined in claim 1,

R is lower alkyl having I to 4 carbon atoms,

R is the same as R excluding hydrogen and represents R when R ishydrogen,

each of R and R is respectively the same as R;,

and R excluding hydrogen and is respectively R when either of R and Rare hydrogen, and

Z is a leaving group.

20. The compound of claim 1 which is lO-chloro-2,7-dimethyl-5H-s-triazolo[ l ,S-d] 1,4]-benzodiazepin- 6(7H)-one.

21. The compound of claim 1 which is lO-chloro-2,5,7-trimethyl-5H-s-triazolo [l,5-d] 1,4]benzodiazepin-6(7H)-one.

22. The compound of claim 1 which is l0-chloro-2,5,6,7-tetramethyl-5H-s-triazolo [1,5-d] 1,4]benzodiazepin-6(7H)-one.

23. A compound of the formula where R R R R and R are as defined inclaim 1, or a pharmaceutically acceptable acid addition salt thereof.24. A compound of the formula where R,,, R R R and R are as defined inclaim 1, or a pharmaceutically acceptable acid addition salt thereof.

2. A pharmaceutically acceptable acid addition salt of a compound ofclaim
 1. 3. A compound of the formula
 4. A compound of the formula
 5. Acompound of the formula
 6. A compound of the formula
 7. A compound ofthe formula
 8. A compound of the formula
 9. A compound of the formula10. A compound of the formula
 11. The compound of claim 1 which is10-chloro-5H-s-triazolo (1, 5-d)(1,4)benzodiazepin-6(7H)-one.
 12. Thecompound of claim 1 which is10-chloro-2-methyl-5H-triazolo(1,5-d)(1,4)benzodiazepin-6(7H)-one. 13.The compound of claim 1 which is10-chloro-7-methyl-5H-s-triazolo(1,5-d)(1,4)benzodiazepin-6(7H)-one. 14.The compound of claim 1 which is5,7-dimethyl-10-chloro-5H-s-triazolo(1,5-d)(1,4)benzodiazepin-6(7H)-one.15. The compound of claim 1 which is10-chloro-5,5,7-trimethyl-5H-s-triazolo(1,5-d)(1,4)benzodiazepin-6(7H)-one.16. A process for preparing a compound of claim 1 which comprises thestep of reacting a compound of the formula
 17. A process for preparing acompound of claim 1 which comprises the step of reacting a compound ofthe formula:
 18. A process for preparing a compound of claim 1 in whichR2 is lower alkyl which comprises the step of reacting a compound of theformula
 19. A process for preparing a compound of the formula
 20. Thecompound of claim 1 which is 10-chloro-2,7-dimethyl-5H-s-triazolo(1,5-d)(1,4)-benzodiazepin-6(7H)-one.
 21. The compound of claim 1 which is10-chloro-2,5,7-trimethyl-5H-s-triazolo (1,5-d)(1,4)benzodiazepin-6(7H)-one.
 22. The compound of claim 1 which is10-chloro-2,5,6,7-tetramethyl-5H-s-triazolo (1,5-d)(1,4)benzodiazepin-6(7H)-one.
 23. A compound of the formula
 24. Acompound of the formula